Social anxiety disorder (SAD) is among the most common psychiatric conditions and is associated with significant distress and dysfunction in affected individuals. Although treatment with cognitive-behavior therapy (CBT) results in some of the best outcomes in the empirical literature for SAD, many patients do not respond to this intervention and most do not achieve remission. Thus, given the prevalence and attendant morbidity of SAD, and its persistence despite treatment, there is a critical need for the development of novel interventions to improve outcome. In CBT, core therapeutic procedures include repeated and prolonged exposure practices to feared social situations, allowing fears to extinguish as patients acquire a sense of safety in the presence of these stimuli. Exposure therapy is based on animal models of extinction of conditioned fears, and recent animal research has mapped some of the core pathways and neurotransmitters involved in fear extinction. D-cycloserine (DCS), an agonist at the glutamatergic NDMA receptor site appears to augment learning in animals and in some human trials facilitating the process of extinction of conditioned fear. Thus, converging evidence from animal models of fear extinction, and from initial studies in humans, including work from our pilot study, indicates that DCS can facilitate CBT of SAD. We are proposing a 4-year study to systematically assess the efficacy of DCS augmentation of CBT for the treatment of SAD. The study comprises a randomized, controlled trial to compare the relative short-term and long-term benefits of 12 CBT sessions that include 5 DCS-augmented (50 mg) sessions with the same CBT protocol that includes 5 placebo-augmented sessions. In addition, we will explore potential mediators and moderators of treatment change. We will randomize a total of 192 patients with the identical protocol followed at each of the sites. We make use of a collaborating team of investigators across 3 treatment sites to help ensure the timely recruitment of adequate numbers of patients, including an ethnically diverse population. This study represents a crucial stage in translating bench research to the clinic, and testing a novel approach for combining pharmacologic and cognitive-behavioral strategies for treating patients. This study addresses an important public health issue by assessing an intervention that may lead to a more efficient and effective application of empirically based psychosocial interventions for the treatment of SAD.